Research

ALS as a systemic disease

Understanding the extra-motor manifestations of ALS

Many people living with motor neuron disease will experience cognitive dysfunction during their disease. In fact, motor neuron disease is now considered part of the same disease spectrum of frontotemporal dementia, characterised by cognitive dysfunction in behaviour, language, fluency and executive functioning. Our group have created several deeply-phenotyped post-mortem tissue cohorts to try to understand what makes some people more susceptible to these non-motor/cognitive symptoms, something that we hope will allow us to open therapeutic avenues for susceptible individuals in the future. Our group are also interested in non-central nervous system manifestations of motor neuron disease. Non-neurological symptoms are common in people with motor neuron disease, and we showed recently that the same pathology that is seen in the brain at post-mortem can be seen in non-central nervous system tissues (particularly gut tissues) many years prior to motor or cognitive symptom onset. This could provide us with a biomarker for early diagnosis and possibly even improve chances for early therapeutic intervention.

Ante-mortem tissue cohort comprised of tissue taken from people with ALS demonstrates non-CNS accumulation of pTDP-43 aggregates prior to symptom onset.Schematic of workflow to identify pTDP-43 aggregates indicative of non-central nervous system (CNS) manifestations of ALS. Lower panel left: cartoon depicting organs and cell types that had evidence of pTDP-43 aggregation in ALS patient non-CNS ante-mortem tissue. Lower panel right: cartoon depicting organs with no evidence of pTDP-43 aggregation in ALS patient non-CNS ante-mortem tissue. From Pattle et al., bioRxiv 2022: 2022.03.17.484805.

Pathomechanisms of protein misfolding

Inflammation & molecular crowding in ALS

One of the unifying pathological features in the majority of neurodegenerative diseases is the presence of aberrantly misfolded intra- and extra-cellular protein aggregates. These aggregates are present in the central nervous system at post-mortem, but our group was the first to show that these aggregates are also present in non-CNS tissues many years prior to neurological symptom onset in motor neuron disease. We are interested in common pathomechanisms that could be driving this aggregation in different CNS and non-CNS organs. Our central hypothesis for this work is that aggregation and cellular dysfunction is precipitated by crowding of the intracellular environment potentiating the aggregation of aggregation-prone proteins and preventing their disassembly. We believe that this could be potentiated by extrinsic pressure on cells, caused by inflammation and extracellular oedema, constricting their environment resulting in compression that reduces cell volume. Indeed, we see distinct inflammatory activation signatures in sequencing data from motor neuron disease patients. Our group is interested in investigating specific mechanisms of inflammation and understanding how these mechanisms could be manipulated therapeutically.

Reciprocal expression changes in regulators of the inflammasome demonstrate distinct differences in coordinated responses to inflammation. (A) Representative micrographs demonstrating spatially resolved expression of NLRP3 in cognitively affected and resilient brain regions using BaseScope in situ hybridisation (ISH) and corresponding protein localisation using immunohistochemistry (IHC). Red arrows indicate neurons with high expression; blue arrows indicate glial cells with high expression; and white arrows indicate no expression. From Banerjee et al., J Pathol 2022; 256(3):262-268.

Clinical & Pre-clinical Data Science

Translational Medicine

As a clinician scientist, I am keen to facilitate the translation of experimental science to the clinic. As part of this research theme, our group regularly perform systematic-reviews and meta-analyses, spanning a wide range of clinical questions, including evaluations of both the preclinical and clinical literature. Data quality assessments and research recommendations are also an integral part of our approach. Examples of previous projects are listed below. This research is particularly useful for undergraduates (clinical and non-clinical), PhD students and early career researchers who want to gain a better understanding of a particular research topic and often results in high-value translational publications. We often have projects ongoing in this area and are happy to design new bespoke projects for individuals to lead on, so get in touch if you are interested.

a PRISMA Diagram detailing each step of the systematic review, with number of studies highlighted as n = x. Reasons for exclusion given in boxes on the right. b Forest plot assessing the utility of CSF TDP-43 as a biomarker for FTD-ALS displaying standardised mean differences (SMD) and 95% confidence intervals (CI) using a random effects model. Study identifiers (author and year of publication) given on left. Heterogeneity calculated using Chi2 and I2 showing significant heterogeneity. Summary statistic (black diamond shows statistically significantly higher TDP-43 in the CSF of FTD-ALS patients compared to controls. c Forest plot assessing the utility of CSF TDP-43 as a biomarker for FTD displaying SMD and 95% CI using a random effects model. Study identifiers (author and year of publication) given on left. Heterogeneity calculated using Chi2 and I2 showing significant heterogeneity. Summary statistic (black diamond shows no statistically significant difference in TDP-43 in the CSF of FTD patients compared to controls. d Forest plot assessing the utility of CSF TDP-43 as a biomarker for FTD-ALS displaying SMD and 95% CI using a random effects model. Study identifiers (author and year of publication) given on left. Heterogeneity calculated using Chi2 and I2 showing significant heterogeneity. Summary statistic (black diamond shows statistically significantly higher TDP-43 in the CSF of ALS patients compared to controls. From Gregory et al., BMC Neurol 2018; 18(1):90.

Here is a list of some of our collaborators, past and present:

Dr. Neil Shneider (Columbia University/Elanour & Lou Gerrig ALS Centre)

Dr. Chris Sibley (University of Edinburgh)

Dr. Mathew Horrocks (University of Edinburgh)

Dr. Hemali Phatnani (New York Genome Centre)

Prof. Sharon Abrahams (University of Edinburgh)

Prof. Gian Gaetano Tartaglia (Italian Institute of Technology; Centre for Human Technologies, Genoa)

Prof. Mark Wilson (University of Wollongong)

Dr. James Longden (e-therapeutics PLC, Edinburgh)

Dr. Valeria Gerbino (Fondazione Santa Lucia, Rome)

Prof. Tom Maniatis (Columbia University)

Prof. Ai Yamamoto (Columbia University)

Prof. Liam Holt (New York University)

Prof. Simon Parson (University of Aberdeen)

Prof. Thomas Bak (University of Edinburgh)

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